The current global outbreak of Clostridium difficile infection exemplifies the major public health threat posed by clostridial toxins. In the western world, C. difficile infection is one of the most prolific causes of bacterial-induced diarrhea and potentially fatal colitis. Two pathogenic enterotoxins, Toxin A and Toxin B, cause the disease. Vancomycin and metronidazole remain readily available treatment options for treating C. difficile infection, but neither is fully effective as is evident by high clinical relapse and fatality rates. Thus, there is an urgent need to find an alternative therapy that preferentially targets the toxins and not the pathogen. Oezguen et al., “Clostridial toxins: Sensing a target in a hostile gut environment” Gut Microbes 3:135-41 (2012). This application describes novel potential therapies.
The dramatic increase in severity of C. difficile-associated disease in North America and Europe over the last decade highlights the clinical prominence of C. difficile 's glucosylating toxins, and is partially due to the spread of new epidemic-associated strains, for example BI/NAP1/027 that produce high amounts of these toxins. Accompanying this surge in disease severity is a rise in recurrent clinical episodes in up to 35% of patients (CDI). DuPont H.L., “The search for effective treatment of Clostridium difficile infection” N Engl J Med 364:473-475 (2011). These unmet clinical issues represent a significant medical and financial challenge to health care systems, and have rekindled interest in improving therapy against this increasingly prevalent pathogen. Oezguen et al., “Clostridial toxins: Sensing a target in a hostile gut environment” Gut Microbes 3:135-41 (2012).
What is needed in the art, and what are described in this application, are safe and effective therapeutic compounds that can effectively inactivate microbial toxins, either systemically or within the localized area of infection. Another beneficial therapeutic approach described in this invention is the use of novel chemical agents that can inhibit toxin production.